This invention relates to a method of treating atherosclerosis in mammals, including humans, with certain estrogen agonists/antagonists.
Myocardial infarction is the leading cause of death in western countries, accounting annually for more than 500,000 deaths in the United States alone. Coronary artery stenosis and the number of diseased vessels are accepted markers of cardiac morbidity and mortality. The rupture of unstable atherosclerotic plaques contributes to nearly 75% of all myocardial infarctions and strokes. However, angiography does not predict future sites of occlusion and or rupture. Recent studies suggest that 72% of coronary events are not of severe calcified, fibrotic lesions but rather from rupture of mildly stenotic lipid rich plaques, often not visible by angiography (Circulation, 1994: 90:4: 2126-2146). Several recent studies have shown that increased macrophage infiltration is associated with erosion of the extracellular matrix of an atherosclerotic lesion, weakening of the lesion cap and increased vulnerability to rupture (Circulation. 1994:90:1669-1678.). It has been suggested that uncontrolled monocyte infiltration leads to excessive lipid accumulation and increased extracellular breakdown of the fibrous cap of the atherosclerotic lesion, thus triggering thrombosis. It has also been suggested that an inhibitor of the pro-inflammatory responses, will enhance plaque stability by preventing excessive monocyte infiltration.
Also, Wiseman, et al. Biochem. Pharm. 45, No. 9, 1851 (1993) have disclosed the role of lipid peroxidation in cardiovascular injury and the development of atherosclerosis. In addition, Wiseman et al. Cancer Letters 66, 61 (1992) have disclosed that droloxifene inhibits lipid peroxidation. Also, U.S. Pat. No. 5,047,431 discloses the use of droloxifene for the treatment of hormone dependent mammary tumors and U.S. Pat. No. 5,254,594 discloses the use of droloxifene for the relief of bone diseases caused by the deficiency of estrogen. U.S. Pat. No. 5,426,123 discloses the lipid lowering effects of droloxifene.
In addition Grainger, et al., Nature Medicine, Vol. 1, No. 10 (October 1995) have disclosed tamoxifen suppresses diet-induced formation of lipid lesions in mouse aorta.
Thus, although there exist a variety of anti-atherosclerotic therapies there is a continuing need and a continuing search in this field of art for alternative therapies for treating atherosclerosis.